The Calpain System

Abstract

Goll, Darrel E., Valery F. Thompson, Hongqi Li, Wei Wei, and Jinyang Cong. The Calpain System. Physiol Rev 83: 731–801, 2003; 10.1152/physrev.00029.2002.—The calpain system originally comprised three molecules: two Ca2+-dependent proteases, μ-calpain and m-calpain, and a third polypeptide, calpastatin, whose only known function is to inhibit the two calpains. Both μ- and m-calpain are heterodimers containing an identical 28-kDa subunit and an 80-kDa subunit that shares 55–65% sequence homology between the two proteases. The crystallographic structure of m-calpain reveals six “domains” in the 80-kDa subunit: 1) a 19-amino acid NH2-terminal sequence; 2) and 3) two domains that constitute the active site, IIa and IIb; 4) domain III; 5) an 18-amino acid extended sequence linking domain III to domain IV; and 6) domain IV, which resembles the penta EF-hand family of polypeptides. The single calpastatin gene can produce eight or more calpastatin polypeptides ranging from 17 to 85 kDa by use of different promoters and alternative splicing events. The physiological significance of these different calpastatins is unclear, although all bind to three different places on the calpain molecule; binding to at least two of the sites is Ca2+ dependent. Since 1989, cDNA cloning has identified 12 additional mRNAs in mammals that encode polypeptides homologous to domains IIa and IIb of the 80-kDa subunit of μ- and m-calpain, and calpain-like mRNAs have been identified in other organisms. The molecules encoded by these mRNAs have not been isolated, so little is known about their properties. How calpain activity is regulated in cells is still unclear, but the calpains ostensibly participate in a variety of cellular processes including remodeling of cytoskeletal/membrane attachments, different signal transduction pathways, and apoptosis. Deregulated calpain activity following loss of Ca2+ homeostasis results in tissue damage in response to events such as myocardial infarcts, stroke, and brain trauma.

Regulatory polymorphisms in the bovine Ankyrin 1 gene promoter are associated with tenderness and intramuscular fat content

“…The calpain family of Ca 2+ -dependent proteases are thus key proteins in the regulation of tenderness [58-60]. Proteins which are reported to be proteolysed by calpains can be classified as kinases/phosphatases, membrane associated proteins, some transcription factors and cytoskeletal proteins which include desmin, gelsolin, myosin, nebulin, spectrins, titin, tropomyosin -for review see [61]. Ankyrin is one of the cytoskeletal proteins proteolysed by members of the calpain family [7,16,61,62].…”

“…Proteins which are reported to be proteolysed by calpains can be classified as kinases/phosphatases, membrane associated proteins, some transcription factors and cytoskeletal proteins which include desmin, gelsolin, myosin, nebulin, spectrins, titin, tropomyosin -for review see [61]. Ankyrin is one of the cytoskeletal proteins proteolysed by members of the calpain family [7,16,61,62]. Since ankyrin has functions in maintaining the structural integrity of, and linkages among myofibrils, the degradation of ankyrin could cause further softening of myofibrils and thus, tenderization.…”

Corticosteroid effects on ventilator-induced diaphragm dysfunction in anesthetized rats depend on the dose administered

“…Binding of calcium to calpain leads to conformational changes of the molecule allowing activation of its catalytic site. An additional important regulator of calpain activity is its endogenous inhibitor calpastatin[18]. Evidence exists that corticosteroids might protect against calpain activation by preventing an increase in cytosolic calcium levels.…”

“…Although the UPP is considered a major proteolytic system in skeletal muscle, it cannot degrade intact myofilaments. Release of myofilaments for subsequent degradadtion by the UPP occurs by the calpain and/or caspase system and may be the rate-limiting step in skeletal muscle proteolysis[18]. …”

Natural history of LGMD2A for delineating outcome measures in clinical trials

“…This enzyme is a skeletal muscle‐specific form of calpains, a family of intracellular calcium‐dependent cysteine proteases mediating their activity through limited proteolysis of various target substrates 6. Within the muscle fiber, calpain 3 is located in at least two regions of the sarcomere (the I‐band and the M‐line), thanks to binding to titin, a giant elastic filamentous protein of the sarcomere 7.…”